SUMMARY Urologic chronic pelvic pain syndromes (UCPPS) cause untold morbidity and are associated with depression. Multidisciplinary Assessment of Pelvic Pain (MAPP) has been very successful during Phase I, and Phase II promises even greater understanding of UCPPS phenotypes and the underlying mechanisms. Our team has contributed to many key Trans-MAPP initiatives, including workgroups focusing on animal models, neuroimaging, and patient-reported outcomes in UCPPS. Here, we seek to build upon these important efforts with innovative studies that go well beyond MAPP I by examining the relationship between UCPPS, its underlying mechanisms, and depression. Our site will recruit into a large Symptom Pattern Study (N = 106 per site) and follow them longitudinally to track the trajectory of pelvic pain, as well as to identify risk factors for symptom flares and exacerbations. As part of the Symptom Pattern Study, patients will be characterized by presenting symptoms, biomarkers, and neuroimaging. Our site-specific proposal includes a number of neuroimaging studies to interrogate brain-periphery connections as well as to study dysregulation in risk-reward circuitry that may be relevant to pelvic pain comorbidities. To better characterize UCPPS symptoms and comorbidities, we also propose to develop a mobile-phone-based app for high- resolution monitoring of UCPPS symptoms, as well as an intense psychiatric phenotyping study in which state-of-the-art interviews are used to understand comorbid diagnoses of UCPPS patients. Finally, we propose a series of mechanistic studies using clinically relevant murine UCPPS models to define the role of TLR4 as an integrator of triggers that drive pain, voiding dysfunction, and anxiety/depression. In summary, these studies will yield a multi-dimensional understanding of UPPS phenotypes and mechanisms that set the stage for individualized and effective therapies.